Study Co-Chairs: Caroline Chung Warren Mason

Symptom Intervention Committee Chair: Charles Loprinzi Rad Onc Co-chairs: Paul Brown Normand Laperriere Med Onc Co-Chair: Glenn Lesser Community Oncology Co-Chair: Christopher Goulet Neurosurgery Co-Chair: Ian Parney Neuroradiology Imaging Co-Chair: Tim Kaufmann Health Outcomes Co-Chair: Terri Armstrong Biomarkers Correlative Co-Chairs: Erik Sulman David Grosshans Statistics: Rui Qin Heshan Liu

Study Co-Chairs:

ALLIANCE A221208: Phase II Randomized Study of

Bevacizumab vs. Steroids (BeSt) for Radionecrosis after Radiosurgery for Brain Mets

!! ~ 10-30% patients develop brain radionecrosis following SRS1

!! Incidence of brain radionecrosis (longer survival, more high-dose RT, SRS, repeat RT)

!! Corticosteroids are effective, but not for all patients

!! Prolonged corticosteroids can be associated with ++ toxicity

Proposed mechanism: VEGF ! vascular permeability ! edema,hypoxia ! white matter

necrosis !Clinical evidence: !! Small studies of bevacizumab for radionecrosis show radiological and

clinical response2-4

1Shaw, E – IJROBP 2000 2Gonzales J – IJROBP 2007 3Wong ET – JCO 2008 4Levin – IJROBP 2011

Bevacizumab

•! Hypothesis: Bevacizumab will provide greater clinical and radiological improvement resulting in greater improvement in the severity of symptoms, neurological and cognitive impairment compared to conservative management with corticosteroids.

Bevacizumab 10 mg/kg IV days 1 and 15 for 1 cycle (30 days) x 4 cycles + corticosteroids

Placebo IV days 1 and 15 for 1 cycle (30 days) x 4 cycles + corticosteroids

Central Imaging review

Cross-over allowed at progression

Symptomatic brain radionecrosis requiring corticosteroids following SRS for brain metastases

Central Imaging review

FU every 2 months (up to 6 months): MR brain + clinical visit with PRO

Randomized phase II study of bevacizumab vs. steroid therapy in patients diagnosed with radionecrosis following radiosurgery.

After 6 months: event monitoring only

Stratified for: Age pathological confirmation baseline MDASI prior WBRT

N= 130, 65 per arm

Drug is provided

!! Acute intracranial/intratumoral hemorrhage

!! Glioma or brain mets from melanoma, RCC !! Non-approved systemic therapies (2 wks

prior to registration or planned < 1 mo after registration)

!! Except: Maintenance herceptin or hormonal therapies OR ‘Approved systemic’ therapies [Appendix]

Inclusion Criteria Exclusion Criteria !! Symptomatic brain radionecrosis

defined by onset of symptoms at 3-24 months post-SRS that requires steroid intervention and meets the following radiological criteria:

•! Lesion quotient < 0.3 1 •! DSC 2- At least 1:

•! rCBV <1.5 •! PSR > 76%

!! Life expectancy > 6 months !! KPS " 60% !! Acceptable organ function (bone

marrow, renal, liver

1Kumar – Radiology 2000 2 Barajas – AJNR 2009

Standard C/I to bevacizumab: •! Major surgical procedure within 28 days or core biopsy

within 7 days •! Pregnant or nursing •! PT INR >1.5 •! Bleeding diathesis, coagulopathy, non-healing wound/

ulcer, bowel obstruction/fistula/GI perforation •! Significant cardiovascular disease •! Central lung met with xs active bleeding

LESION QUOTIENT = maximal cross-sectional area of T2-w hyperintensity maximal cross-sectional area of T1-gad enhancement

Stockham et al. (n = 51 patients) Stockham-JNeurooncol2012

Dequesada – Neurosurgery 2008

Tumor (LQ>0.6) Radionecrosis (LQ <0.3)

Sensitivity 59% 8% Specificity 41% 91% PPV 62% 25% NPV 39% 73%

Kumar – Radiology 2000

LQ > 0.6 in tumor LQ < 0.3 in 80% of radionecrosis

LESION QUOTIENT = maximal cross-sectional area of T2-w hyperintensity maximal cross-sectional area of T1-gad enhancement

Kumar – Radiology 2000

Barajas – AJNR 2009

Eligibility Criteria: rCBV <1.5 PSR > 76%

Tumor Radionecrosis

!! Primary Endpoint !! Improvement in patient-reported symptoms measured by MDASI-BT !

global symptom score (baseline then weeks 2, 4, 6, and 8)

!! Secondary Endpoint(s) !! Toxicities: CTCAE version 4.0 & DSQ-C !! QoL: LASA, MDASI-BT symptoms and interference scores !! PFS (progression = restart higher dose steroids or alternative tx) !! Time to maximum radiographic response !! Corticosteroid requirements

! Correlative Endpoints:!! Biofluid Biomarkers: angiogenic factors:

"! Angiogenic markers: VEGF-A, B, C, D, angiopoietin-1 and 2, PDGF "! inflammatory cytokines (TNF-#, TGF-$, IL1, and IL6) "! genetic markers (Apo E)

!! Imaging Biomarker Measures: DWI (ADC), DCE (Ktrans, iAUC)

!!Central study activation April 29, 2016

!!Note: !!Drug is provided for initial randomization &

cross-over !!Correlative biomarker studies are optional

!!Contact: cchung3@mdanderson.org